Association of germline variants in the APOBEC3 region with cancer risk and enrichment with APOBEC-signature mutations in tumors

Middlebrooks, Candace D.; Banday, Abdul Rouf; Matsuda, Konichi; Udquim, Krizia Ivana; Onabajo, Olusegun O.; Paquin, Ashley; Figueroa, Jonine D.; Zhu, Bin; Koutros, Stella; Kubo, Michiaki; Shuin, Taro; Freedman, Neal D.; Kogevinas, Manolis; Malats, Núria; Chanock, Stephen J.; García-Closas, Montserrat; Silverman, Debra T.; Rothman, Nathaniel; Prokunina‐Olsson, Ludmila

doi:10.1038/ng.3670

Cited by 164 publications

(232 citation statements)

References 57 publications

(83 reference statements)

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“…3C). While a recent study reported an enrichment of kataegis -related mutation pattern in tumors presenting common APOBEC3 variants, 40 our analysis shown that APOBEC3 mutations were linked to the total number of mutations in the tumor (Table 3B), and the latter and kataegis were associated with each other (Table 2). APOBEC3 mutations were also independently correlated with MSI, MMR alterations and POLE mutations (Table 3B).…”

Section: Discussioncontrasting

confidence: 41%

High expression of PD-1 ligands is associated with kataegis mutational signature and APOBEC3 alterations

2017

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Immunotherapy with checkpoint inhibitors, such as antibodies blocking the programmed cell-death receptor-1 (PD-1), has resulted in remarkable responses in patients having traditionally refractory cancers. Although response to PD-1 inhibitors correlates with PD-1 ligand (PD-L1 or PD-L2) expression, PD-1 ligand positivity represents only a part of the predictive model necessary for selecting patients predisposed to respond to immunotherapy. We used all genomic, transcriptomic, proteomic and phenotypic data related to 8,475 pan-cancer samples available in The Cancer Genome Atlas (TCGA) and conducted a logistic regression analysis based on a large set of variables, such as microsatellite instability (MSI-H), mismatch repair (MMR) alterations, polymerase δ (POLD1) and polymerase ε (POLE) mutations, activation-induced/apolipoprotein-B editing cytidine deaminases (AID/APOBEC) alterations, lymphocyte markers and mutation burden estimates to determine independent factors that associate with PD-1 ligand overexpression. PD-1 ligand overexpression was independently and significantly correlated with overexpression of and mutations in APOBEC3 paralogs. Additionally, while high tumor mutation burden and overexpression of PD-L1 have been previously correlated with each other, we demonstrate that the specific mutation pattern caused by APOBEC enzymes and called kataegis—rather than overall mutation burden, MSI-H or MMR alterations—correlates independently with PD-L1/PD-L2 expression. These observations suggest that APOBEC3 alterations, APOBEC3 overexpression and kataegis play an important role in the regulation of PD-1 ligand overexpression, and thus, their relationship with immune checkpoint inhibitor response warrants exploration.

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Section: Discussioncontrasting

confidence: 41%

High expression of PD-1 ligands is associated with kataegis mutational signature and APOBEC3 alterations

2017

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“…In our study, the frequency of the TP53 gene mutation was also higher in tumors with high APOBEC3B mRNA expression than in those with low or lacking APOBEC3B mRNA expression. Although the mechanism of the upregulation of APOBEC3B mRNA expression has not been been fully elucidated, a recent study showed the induction of APOBEC3B in vitro by environmental factors such as DNA damage and viral infection [24]. …”

Section: Discussionmentioning

confidence: 99%

Expression of APOBEC3B mRNA in Primary Breast Cancer of Japanese Women

et al. 2016

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Recent studies have identified the apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3B (APOBEC3B) as a source of mutations in various malignancies. APOBEC3B is overexpressed in several human cancer types, including breast cancer. In this study, we analyzed APOBEC3B mRNA expression in 305 primary breast cancers of Japanese women using quantitative reverse transcription-PCR, and investigated the relationships between the APOBEC3B mRNA expression and clinicopathological characteristics, prognosis, and TP53 mutations. The expression of APOBEC3B mRNA was detected in 277 tumors and not detected in 28 tumors. High APOBEC3B mRNA expression was significantly correlated with ER- and PR-negativity, high grade and high Ki67 index. The APOBEC3B mRNA expression was highest in the triple-negative and lowest in the hormone receptor-positive/HER2-negative subtypes. The TP53 gene was more frequently mutated in the tumors with high APOBEC3B mRNA expression. High APOBEC3B mRNA expression was significantly associated with poor recurrence-free survival in all cases and the ER-positive cases. These findings were almost consistent with the previous reports from the Western countries. In conclusion, high APOBEC3B mRNA expression was related to the aggressive phenotypes of breast cancer, high frequency of TP53 mutation and poor prognosis, especially in ER-positive tumors.

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“…3,4 Recent studies have linked cancer progression and recurrence to A3 activity. [5][6][7][8][9] A3 proteins have specific substrate sequence preferences, and analyses of some cancer genomes have shown an enrichment of A3 mutation signatures. [10][11][12][13][14][15] Recent evidence suggests that APOBEC3B (A3B) is an important driver of tumor progression in the A3 family.…”

Section: Introductionmentioning

confidence: 99%

Determinants of Substrate Specificity in APOBEC3B

Wagner

Demir²,

Carpenter³

et al. 2018

Preprint

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APOBEC3B (A3B) is a newly discovered driver of mutation in many cancers. We use computational tools to revert a recent crystal structure of an A3B construct to its native sequence, and run molecular dynamics simulations to study its underlying dynamics and substrate recognition mechanisms. The A3B oligonucleotide substrate simulations show a series of dynamic substrate protein contacts that correlate with previous work on A3B substrate selectivity. A second series of simulations in which the target cytosine nucleotide was computationally mutated from a deoxyribose to a ribose showed a change in sugar ring pucker, leading to a rearrangement of the binding site and revealing a potential intermediate in the binding pathway. Finally, apo simulations of A3B beginning in the open state experience a rapid and consistent closure of the binding site, reaching a conformation incompatible with substrate binding. These simulations agree with previous experimental studies, and we report the atomistic details of these events to further therapeutic studies on A3B. IntroductionThe APOBEC3 (A3) family of cytidine deaminases is a recently discovered endogenous source of mutation in cancer. 1,2 Previously, A3 proteins were studied in the context of their interactions with viruses and efforts were undertaken to discover small molecules that modulate the mutational activities of the virally restrictive APOBEC3G enzyme. 3,4 Recent studies have linked cancer progression and recurrence to A3 activity. 5-9 A3 proteins have specific substrate sequence preferences, and analyses of some cancer genomes have shown an enrichment of A3 mutation signatures. [10][11][12][13][14][15] Recent evidence suggests that APOBEC3B (A3B) is an important driver of tumor progression in the A3 family. 16,17

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Association of germline variants in the APOBEC3 region with cancer risk and enrichment with APOBEC-signature mutations in tumors

Cited by 164 publications

References 57 publications

High expression of PD-1 ligands is associated with kataegis mutational signature and APOBEC3 alterations

High expression of PD-1 ligands is associated with kataegis mutational signature and APOBEC3 alterations

Expression of APOBEC3B mRNA in Primary Breast Cancer of Japanese Women

Determinants of Substrate Specificity in APOBEC3B

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